Anopheline mosquitoes transmit malaria, the world's most devastating parasitic disease, of which Anopheles gambiae is the principal vector for malaria in Sub-Saharan Africa. Different populations of mosquitoes vary widely in how readily they become infected with malaria parasites, while some strains do not transmit malaria at all. The mosquitoes' innate immune system is a significant factor that may influence the level of malaria infection; in particular the thioester-containing protein 1 (TEP1) targets malaria parasite for destruction during their initial invasion of the body cavity. The TEP1 gene varies significantl across mosquito populations with two major classes of alleles, TEP1*S and TEP1*R, that have been shown to directly influence the susceptibility to P. falciparum. In this project we will study the structure-function relationship between TEP1 alleles and their interaction with a mosquito-specific family of leucine-rich repeat proteins, the LRIM1/APL1 family. We will also study the diversity of structure and function associated with three closely-related LRR proteins APL1A, APL1B and APL1C, that influence the specificity of the TEP1 immune response. Finally, we will study the structure and function of three CLIP domain serine protease homologs (SPHs) that regulate downstream effects of TEP1 deposition, specifically melanization. The results of this project will shed light on the mechanism of mosquitoes' natural immunity to malaria infection and support the development of new vector-based transmission-blocking strategies.